Non-Hodgkin's Lymphoma (NHL) killed 20,000 people in 2009 and 66,000 new cases were identified (Jemal et al. 2009). NHL comprises a group of heterogeneous lymphoid malignancies for which conventional chemo- and radiotherapy approaches are rarely curative and many lymphomas relapse within the first year. Newer drugs such as proteasome, cell-cycle-dependent kinase and histone deacetylase inhibitors show promising results in lymphoma therapy, but are non-specific, thereby causing unwanted effects in non-lymphoma tissues such as nausea, vomiting, diarrhea, dehydration, cardiac dysrhythmias, myelosuppression, deep vein thrombosis, pulmonary embolism, and neuropathy. Therefore, a more targeted approach is needed.
Most NHLs are of B cell origin (Kueppers 2005). Diffuse Large B Cell Lymphoma (DLBCL) is the most common type of NHL (Mackay & Schneider 2009). Other lymphoma subtypes often transform into it when they progress. Patients treated with chemo- or radiotherapy often in combination with Rituxumab often respond well initially (Friedberg & Fisher 2008), nevertheless, approximately 50% of DLBCL patients relapse within 2 to 3 years of treatment and require additional therapy such as stem cell transplantation, which is often not curative (Friedberg & Fisher 2008; Feugier et al. 2005; Friedberg & Fisher 2006). Representing 6% of all NHL, Mantle cell lymphoma (MCL) is a relatively rare cancer. However, the clinical evolution of MCL is aggressive, with the lowest 5 year survival rate of any type of lymphoma, and is characterized with poor response to conventional therapeutic regimens (Campo et al. 1999).
A feature of many types of B cell lymphomas is the constitutive expression of oncogenes. Oncogenes are transcription factors, anti-apoptotic genes or genes involved in the cell cycle that are the result of reciprocal chromosomal translocation and mutations. When overexpressed, such genes result in uncontrolled cell proliferation, survival of malignant cells and protection against ionizing radiation and many commonly used chemotherapeutics (Kueppers 2005). Many NHLs, including MCL and DLBCL overexpress genes such as Bcl6, STAT3, c-myc, Bcl2, syk, and Cyclin family members such as Cyclin D1, Cyclin D2 and Cyclin E2(Monti et al. 2005, Shaffer et al. 2006).
Anti-apoptotic Bcl2 gene is translocated in 85% of follicular lymphoma and in 15-30% of DLBCL (Bakhshi et al. 1985). Its overexpression correlates with poor prognosis in NHL patients due to the prolonged survival of the cancer cells (Reed 1996). Additionally, there is evidence that elevated expression of Bcl2 confers multidrug resistance to cells (Makin and Hickman 2000, Domen et al. 1998) and thus provides protection against radiation therapy and commonly used chemotherapeutics.
In 15% of DLBCL and 100% of Burkitt's lymphoma, the oncogene c-myc shows genetic alterations. Cyclin D1 (CCND1), which is involved in cell cycle regulation, is translocated in 95% of MCL. Patients with truncated versions of the Cyclin D1 gene have poor prognosis (Chen et al. 2008). Constitutive expression of STAT3, a transcription factor, deregulates cell cycle progression, apoptosis, angiogenesis and tumor cell evasion of the immune system (Yu and Jove 2004; Yu et al. 2009). The activated B cell subgroup of DLBCL and MCL depends on overexpression of STAT3 for cell survival and proliferation (Ding et al. 2008; Lai et al. 2003).
Knockdown of such oncogenes in B cells by RNA interference (RNAi) may be a promising approach for treating B cell lymphomas. RNAi is a conserved endogenous mechanism in which small interfering RNAs (siRNAs) suppress target-specific gene expression by promoting mRNA degradation. There are many potential uses for siRNAs in a clinical setting, for example, in developing therapeutic agents. However, there are several challenges in using siRNAs in vivo, including poor stability, potential for off-target effects and ensuring specific delivery to the correct tissue or cells.